Depot formulations

ABSTRACT

Disclosed are formulations and related methods that comprise a non-polymeric, non-water soluble high viscosity liquid carrier material having a viscosity of at least 5,000 cP at 37° C. that does not crystallize neat under ambient or physiological conditions; a specified linear polymer comprising lactide repeat units; and one or more solvents that have a solvent capacity.

RELATED APPLICATIONS

The present application is a Continuation of application Ser. No.13/790,902, filed Mar. 8, 2013, which is a Continuation of applicationSer. No. 12/152,764, filed May 16, 2008, which is a non-provisional ofProvisional Application No. 60/930,739, filed May 18, 2007. Thedisclosures of application Ser. Nos. 13/790,902 and 12/152,764 areexpressly incorporated by reference herein their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to formulations comprising non-polymeric,non-water soluble high viscosity liquid carrier materials, linearpolymers and one or more solvents. More particularly, the inventionrelates to such formulations and their use in biologically activesubstance delivery.

Description of Related Art

There has been extensive research in the area of biodegradablecontrolled release systems for bioactive compounds. Biodegradablematrices for drug delivery are useful because they obviate the need toremove the drug-depleted device.

The most common matrix materials for drug delivery are polymers. Thefield of biodegradable polymers has developed rapidly since thesynthesis and biodegradability of potylactic acid was reported byKulkarni et al., in 1966 (“Polylactic acid for surgical implants,” Arch.Surg., 93:839). Examples of other polymers which have been reported asuseful as a matrix material for delivery devices include polyanhydrides,polyesters such as polyglycolides and polylactide-co-glycolides,polyamino acids such as polylysine, polymers and copolymers ofpolyethylene oxide, acrylic terminated polyethylene oxide, polyamides,polyurethanes, polyorthoesters, polyacrylonitriles, andpolyphosphazenes. See, for example, U.S. Pat. Nos. 4,891,225 and4,906,474 to Langer (polyanhydrides), U.S. Pat. No. 4,767,628 toHutchinson (polylactide, 1 polylactide-co-glycolide acid), and U.S. Pat.No. 4,530,840 to Tice, et al. (polylactide, polyglycolide, andcopolymers).

Degradable materials of biological origin are well known, for example,crosslinked gelatin. Hyaluronic acid has been crosslinked and used as adegradable swelling polymer for biomedical applications (U.S. Pat. No.4,957,744 to Della Valle et al.; (1991) “Surface modification ofpolymeric biomaterials for reduced thrombogenicity,” Polym. Mater. Sci.Eng., 62:731-735).

Biodegradable hydrogels have also been developed for use in controlleddrug delivery as carriers of biologically active materials such ashormones, enzymes, antibiotics, antineoplastic agents, and cellsuspensions. Temporary preservation of functional properties of acarried species, as well as the controlled release of the species intolocal tissues or systemic circulation, have been achieved. See forexample, U.S. Pat. No. 5,149,543 to Cohen. Proper choice of hydrogelmacromers can produce membranes with a range of permeability, pore sizesand degradation rates suitable for a variety of applications in surgery,medical diagnosis and treatment.

Many dispersion systems are currently in use as, or being explored foruse as, carriers of substances, particularly biologically activecompounds. Dispersion systems used for pharmaceutical and cosmeticformulations can be categorized as either suspensions or emulsions.Suspensions are defined as solid particles ranging in size from a fewnanometers up to hundreds of microns, dispersed in a liquid medium usingsuspending agents. Solid particles include microspheres, microcapsules,and nanospheres. Emulsions are defined as dispersions of one liquid inanother, stabilized by an interfacial film of emulsifiers such assurfactants and lipids. Emulsion formulations include water in oil andoil in water emulsions, multiple emulsions, microemulsions,microdroplets, and liposomes. Microdroplets are unilamellar phospholipidvesicles that consist of a spherical lipid layer with an oil phaseinside, as defined in U.S. Pat. Nos. 4,622,219 and 4,725,442 issued toHaynes. Liposomes are phospholipid vesicles prepared by mixingwater-insoluble polar lipids with an aqueous solution. The unfavorableentropy caused by mixing the insoluble lipid in the water produces ahighly ordered assembly of concentric closed membranes of phospholipidwith entrapped aqueous solution.

U.S. Pat. No. 4,938,763 to Dunn, et al., discloses a method for formingan implant in situ by dissolving a non-reactive, water insolublethermoplastic polymer in a biocompatible, water soluble solvent to forma liquid, placing the liquid within the body, and allowing the solventto dissipate to produce a solid implant. The polymer solution can beplaced in the body via syringe. The implant can assume the shape of itssurrounding cavity. In an alternative embodiment, the implant is formedfrom reactive, liquid oligomeric polymers which contain no solvent andwhich cure in place to form solids, usually with the addition of acuring catalyst.

U.S. Pat. No. 5,747,058 to Tipton et al., discloses a composition forthe controlled release of substances that includes: (i) a non-polymeric,non-water soluble liquid carrier material (HVLCM) of viscosity of atleast 5,000 cP at 37.degree. C. that does not crystallize neat underambient or physiological conditions; and (ii) a substance to bedelivered.

While a number of materials have been evaluated for use in thecontrolled delivery of substances, there remains a need for formulationsand methods that provide controlled delivery of biologically activesubstances with low toxicity.

BRIEF SUMMARY OF THE INVENTION

In an aspect, the invention relates to formulations comprising: (i) anon-polymeric, non-water soluble high viscosity liquid carrier materialhaving a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer; and (iii) one or more solvents that have asolvent capacity; wherein the linear polymer has a weight averagemolecular weight less than or equal to about 15,000 Daltons, and wherein(a) R satisfies the following: about 0.55≤R≤about 0.95; (b) when Rsatisfies the following: about 0.55≤R≤0.85, the solvent capacity of theone or more solvents is greater than or equal to about 20%; and (c) whenR satisfies the following: greater than about 0.85 to about 0.95, thesolvent capacity of the one or more solvents is greater than or equal toabout 10%.

In another aspect, the invention relates to formulations comprising: (i)a non-polymeric, non-water soluble high viscosity liquid carriermaterial having a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer; and (iii) one or more solvents that have asolvent capacity; wherein the linear polymer has a weight averagemolecular weight less than or equal to about 15,000 Daltons, andwherein: (a) R satisfies the following: about 0.55≤R≤0.85; and (b) thesolvent capacity of the one or more solvents is greater than or equal toabout 20%.

In yet another aspect, the invention relates to formulations comprising:(i) a non-polymeric, non-water soluble high viscosity liquid carriermaterial having a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer; and (iii) one or more solvents that have asolvent capacity; wherein the linear polymer has a weight averagemolecular weight less than or equal to about 15,000 Daltons, and wherein(a) R satisfies the following: greater than about 0.85 to about 0.95;and (b) the solvent capacity of the one or more solvents is greater thanor equal to about 10%.

In still another aspect, the invention relates to formulationscomprising: (i) a non-polymeric, non-water soluble high viscosity liquidcarrier material having a viscosity of at least 5,000 cP at 37° C. thatdoes not crystallize neat under ambient or physiological conditions;(ii) a linear polymer comprising lactide repeat units, wherein thelinear polymer possesses a ratio R of lactide repeat units to totalrepeat units in the linear polymer, wherein R satisfies the following:about 0.55≤R≤about 0.95; and (iii) one or more solvents present in anamount ranging from about one weight percent up to about 35 weightpercent, based on the total weight of the formulation; wherein thelinear polymer has a weight average molecular weight less than or equalto about 15,000 Daltons, and wherein the one or more solvents compriseethanol, ethyl lactate, propylene carbonate, glycofurol,N-methylpyrrolidone, 2-pyrrolidone, benzyl benzoate, miglyol, propyleneglycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,benzyl alcohol, triacetin, dimethylformamide, dimethylsulfoxide,tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and/or1-dodecylazacycloheptan-2-one, and combinations of any of the above.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified materials or process parameters as such may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments of the inventiononly, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entiretyfor all purposes.

As used in this specification and the appended claims, the singularforms “a,” “an” and “the” include plural referents unless the contentclearly dictates otherwise. For example, reference to “a polymer”includes a mixture of two or more such molecules, reference to “asolvent” includes a mixture of two or more such compositions, referenceto “an adhesive” includes mixtures of two or more such materials, andthe like.

A. Introduction

Surprisingly, the inventors have found that the problems in the art maybe addressed by providing formulations that comprise: (i) anon-polymeric, non-water soluble high viscosity liquid carrier materialhaving a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer; and (iii) one or more solvents that have asolvent capacity; wherein the linear polymer has a weight averagemolecular weight less than or equal to about 15,000 Daltons, and wherein(a) R satisfies the following: about 0.55≤R≤about 0.95; (b) when Rsatisfies the following: about 0.55≤R≤0.85, the solvent capacity of theone or more solvents is greater than or equal to about 20%; and (c) whenR satisfies the following: greater than about 0.85 to about 0.95, thesolvent capacity of the one or more solvents is greater than or equal toabout 10%.

Surprisingly, the inventors further have found that the problems in theart may be addressed by providing formulations that comprise: (i) anon-polymeric, non-water soluble high viscosity liquid carrier materialhaving a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer; and (iii) one or more solvents that have asolvent capacity; wherein the linear polymer has a weight averagemolecular weight less than or equal to about 15,000 Daltons, andwherein: (a) R satisfies the following: about 0.55≤R≤0.85; and (b) thesolvent capacity of the one or more solvents is greater than or equal toabout 20%.

Additionally surprisingly, the inventors have found that the problems inthe art may be addressed by providing formulations that comprise: (i) anon-polymeric, non-water soluble high viscosity liquid carrier materialhaving a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer; and (iii) one or more solvents that have asolvent capacity; wherein the linear polymer has a weight averagemolecular weight less than or equal to about 15,000 Daltons, and wherein(a) R satisfies the following: greater than about 0.85 to about 0.95;and (b) the solvent capacity of the one or more solvents is greater thanor equal to about 10%.

In addition, surprisingly, the inventors have found that the problems inthe art may be addressed by providing formulations that comprise: (i) anon-polymeric, non-water soluble high viscosity liquid carrier materialhaving a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions; (ii) alinear polymer comprising lactide repeat units, wherein the linearpolymer possesses a ratio R of lactide repeat units to total repeatunits in the linear polymer, wherein R satisfies the following: about0.55≤R≤about 0.95; and (iii) one or more solvents present in an amountranging from about one weight percent up to about 35 weight percent,based on the total weight of the formulation; wherein the linear polymerhas a weight average molecular weight less than or equal to about 15,000Daltons, and wherein the one or more solvents comprise ethanol, ethyllactate, propylene carbonate, glycofurol, N-methylpyrrolidone,2-pyrrolidone, benzyl benzoate, miglyol, propylene glycol, acetone,methyl acetate, ethyl acetate, methyl ethyl ketone, benzyl alcohol,triacetin, dimethylformamide, dimethylsulfoxide, tetrahydrofuran,caprolactam, decylmethylsulfoxide, oleic acid, and/or1-dodecylazacycloheptan-2-one, and combinations of any of the above.

Linear polymers according to the invention can be used to alter therelease profile of the biologically active substance to be delivered, toadd integrity to the formulation, or to otherwise modify the propertiesof the formulation. Such linear polymers according to the inventioncomprise lactide repeat units. An example of such a polymer ispoly(lactide-co-glycolide). The ratio R, which is the ratio of lactiderepeat units to total repeat units in the linear polymer, is given inthe “R column” of Table 1.

An important consideration in development of formulations according tothe invention is the miscibility or solubility of the polymer in theformulation with the HVLCM. In situations where the polymer is notmiscible or soluble in the formulation with the HVLCM, phase separationof the polymer and the HVLCM may occur. Once this occurs, it may be verydifficult to remix the polymer and the HVLCM, especially at the point ofuse. Should improper remixing of the formulation occur, it might notrelease drug in a desired manner. Additionally, the formulations mightbe difficult to administer. Accordingly, formulations that have highmiscibility or solubility of the polymer in the formulation with theHVLCM are desirable.

The inventive formulations possess this high miscibility or solubilityof the linear polymer in the formulation with the HVLCM. As can be seenby inspecting Table 1, not all formulations comprising linear polymers,HVLCMs, and solvents result in useful formulations. The formulationslisted as “Comparative Formulations” are examples of formulations thatwere not considered to be useful in the context of the presentinvention. In contrast, the inventive embodiments, such as thoseexemplified in Table 1, are useful and exhibit little if any phaseseparation.

The effect of solvent capacity can be seen, for instance, by examiningFormulation 6, which exhibits acceptable solubility behavior. ThisFormulation comprises 55 wt % sucrose acetate isobutyrate (SAIB), 25 wt% NMP, and 20 wt % of a poly (lactide-co-glycolide) (PLGA) having an Rof 0.65 and a Mw of 5300. Formulation 6 has a solvent capacity of 25 wt%. By way of comparison, Formulations C11 and C12 are also presented.Formulation C11 comprises 55 wt % sucrose acetate isobutyrate (SAIB), 20wt % NMP, 5 wt % of DMSO, and 20 wt % of a poly (lactide-co-glycolide)(PLGA) having an R of 0.65 and a Mw of 5300. Likewise, Formulation C12comprises 55 wt % sucrose acetate isobutyrate (SAIB), 20 wt % NMP, 5 wt% of benzyl benzoate, and 20 wt % of a poly (lactide-co-glycolide)(PLGA) having an R of 0.65 and a Mw of 5300. Formulations C11 and C12comprise less than 25 wt % NMP, and are inadequate with respect to theirsolubility performance. Therefore, the formulations C11 and C12 do notmeet the solvent capability requirements and are thus not inventiveembodiments of the present invention.

Another way of understanding solvent capacity is shown in Examples 7 and8. These Examples show how it is possible to determine the solventcapacity for the inventive formulations. This is performed for twoadditional solvent systems, besides the baseline NMP solvent system, andin two different embodiments of the inventive formulations.

Examples 9 and 10 show embodiments of the inventive formulations thatcomprise biologically active substances.

The invention will now be described in more detail.

Definitions

All percentages are weight percent unless otherwise noted.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes and/or reproduced fully herein. The discussionof references herein is intended merely to summarize the assertions madeby their authors and no admission is made that any reference constitutesprior art. Applicants reserve the right to challenge the accuracy andpertinence of the cited references.

The present invention is best understood by reference to the followingdefinitions, the drawings and exemplary disclosure provided herein.

“Administering” or “administration” means providing a drug to a subjectin a manner that is pharmacologically useful.

“Biologically active substance” means molecule(s) including a drug,peptide, protein, carbohydrate (including monosaccharides,oligosaccharides, and polysaccharides), nucleoprotein, mucoprotein,lipoprotein, synthetic polypeptide or protein, or a small moleculelinked to a protein, glycoprotein, steroid, nucleic acid (any form ofDNA, including cDNA, or RNA, or a fragment thereof), nucleotide,nucleoside, oligonucleotides (including antisense oligonucleotides),gene, lipid, hormone, mineral supplement, vitamin including vitamin Cand vitamin E, or combinations of any of the above, that cause(s) abiological effect when administered in vivo to an animal, including butnot limited to birds and mammals, including humans.

Drug means any substance used internally or externally as a medicine forthe treatment, cure, or prevention of a disease or disorder, andincludes but is not limited to immunosuppressants, antioxidants,anesthetics, chemotherapeutic agents, steroids (including retinoids),hormones, antibiotics, antivirals, antifungals, antiproliferatives,antihistamines, anticoagulants, antiphotoaging agents, melanotropicpeptides, nonsteroidal and steroidal anti-inflammatory compounds,antipsychotics, and radiation absorbers, including UV-absorbers.

The term biologically active substance also includes agents such asinsecticides, pesticides, fungicides, rodenticides, and plant nutrientsand growth promoters.

In one embodiment, the formulation is a vaccine and the substance to bedelivered is an antigen. The antigen can be derived from a cell,bacteria, or virus particle, or portion thereof. As defined herein,antigen may be a protein, peptide, polysaccharide, glycoprotein,glycolipid, nucleic acid, or combination thereof, which elicits animmunogenic response in an animal, for example, a mammal, bird, or fish.As defined herein, the immunogenic response can be humoral orcell-mediated. In the event the material to which the immunogenicresponse is to be directed is poorly antigenic, it may be conjugated toa carrier such as albumin or to a hapten, using standard covalentbinding techniques, for example, with one of the several commerciallyavailable reagent kits.

Examples of preferred antigens include viral proteins such as influenzaproteins, human immunodeficiency virus (HIV) proteins, and hepatitis A,B, or C proteins, and bacterial proteins, lipopolysaccharides such asgram negative bacterial cell walls and Neisseria gonorrhea proteins, andparvovirus.

Non-limiting examples of pharmacological materials includeanti-infectives such as nitrofurazone, sodium propionate, antibiotics,including penicillin, tetracycline, oxytetracycline, chlorotetracycline,bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin,chloramphenicol, erythromycin, and azithromycin; sulfonamides, includingsulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,sulfamerazine, and sulfisoxazole, and anti-virals including idoxuridine;antiallergenics such as antazoline, methapyritene, chlorpheniramine,pyrilamine prophenpyridamine, hydrocortisone, cortisone, hydrocortisoneacetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone,triamcinolone, medrysone, prednisolone, prednisolone 21-sodiumsuccinate, and prednisolone acetate; desensitizing agents such asragweed pollen antigens, hay fever pollen antigens, dust antigen andmilk antigen; vaccines such as smallpox, yellow fever, distemper, hogcholera, chicken pox, antivenom, scarlet fever, dyptheria toxoid,tetanus toxoid, pigeon pox, whooping cough, influenzae rabies, mumps,measles, poliomyelitic, and Newcastle disease; decongestants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanticholinesterases such as pilocarpine, esperine salicylate, carbachol,diisopropyl fluorophosphate, phospholine iodide, and demecarium bromide;parasympatholytics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; sympathomimetics such as epinephrine; sedatives andhypnotics such as pentobarbital sodium, phenobarbital, secobarbitalsodium, codeine, (a-bromoisovaleryl) urea, carbromal; psychic energizerssuch as 3-(2-aminopropyl) indole acetate and 3-(2-aminobutyl) indoleacetate; tranquilizers such as reserpine, chlorpromayline, andthiopropazate; androgenic steroids such as methyl-testosterone andfluorymesterone; estrogens such as estrone, 17-.beta.-estradiol, ethinylestradiol, and diethyl stilbestrol; progestational agents such asprogesterone, megestrol, melengestrol, chlormadinone, ethisterone,norethynodrel, 19-norprogesterone, norethindrone, medroxyprogesteroneand 17-.beta.-hydroxy-progesterone; humoral agents such as theprostaglandins, for example PGE.sub.1, PGE.sub.2 and PGF.sub.2;antipyretics such as aspirin, sodium salicylate, and salicylamide;antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide; antimalarials such as the 4-aminoquinolines,8-aminoquinolines, chloroquine, and pyrimethamine, antihistamines suchas diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, andchlorphenazine; cardioactive agents such as dibenzhydroflume thiazide,flumethiazide, chlorothiazide, and aminotrate; antipsychotics includingtypical and atypical antipsychotics, wherein the atypical antipsychoticscomprise risperidone, paliperidone, or olanzapine; nutritional agentssuch as vitamins, natural and synthetic bioactive peptides and proteins,including growth factors, cell adhesion factors, cytokines, andbiological response modifiers; together with pharmaceutically acceptablesalts and polymorphs of the above.

The biologically active substance is included in the composition in anamount sufficient to deliver to the host animal or plant an effectiveamount to achieve a desired effect. The amount of biologically activesubstance incorporated into the composition depends upon the desiredrelease profile, the concentration of biologically active substancerequired for a biological effect, and the desired period of release ofthe biologically active substance.

The concentration of biologically active substance in the compositionwill also depend on absorption, inactivation, and excretion rates of thebiologically active substance as well as other factors known to those ofskill in the art. It is to be noted that dosage values will also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the inventive formulations, and that the concentrationranges set forth herein are exemplary only and are not intended to limitthe scope or practice of the claimed invention. The formulations may beadministered in one dosage, or may be divided into a number of smallerdoses to be administered at varying intervals of time.

The biologically active substance is typically present in theformulations in the range from about 0.5 percent to about 30 percent byweight relative to the total weight of the formulations, and moretypically, between approximately 1 percent to about 20 percent byweight, and more. Another preferred range is from about 2 percent toabout 10 percent by weight. For very active biologically activesubstances, such as growth factors, preferred ranges are less than 1% byweight, and less than 0.0001%.

“Formulation” means a pharmaceutical composition useful in the practiceof this invention.

“Linear” means a polymer in which the molecules form long chainssubstantially without branches or cross-linked structures.

“Non-polymeric, non-water soluble high viscosity liquid carrier materialhaving a viscosity of at least 5,000 cP at 37° C. that does notcrystallize neat under ambient or physiological conditions” means a highviscosity liquid carrier material (“HVLCM”) that is non-polymeric,non-water soluble, and has a viscosity of at least 5,000 cP; preferablyat least 10,000, 15,000; 20,000; 25,000 or even 50,000 cP; at 37° C.that does not crystallize neat under ambient or physiologicalconditions. The term non-water soluble refers to a material that issoluble in water to a degree of less than one percent by weight underambient conditions.

In a preferred embodiment, the HVLCM significantly decreases inviscosity when mixed with a solvent to form a low viscosity liquidcarrier material (“LVLCM”) that can be mixed with a substrate forcontrolled delivery. The LVLCM/substrate composition is typically easierto place in the body than a HVLCM/substrate composition, because itflows more easily into and out of syringes or other implantation means,and can easily be formulated as an emulsion. The LVLCM can have anydesired viscosity. It has been found that a viscosity range for theLVLCM of less than approximately 2000 cP, and more particularly lessthan 1000 cP, is typically useful for in vivo applications.

In a preferred embodiment, sucrose acetate isobutyrate (“SAIB”), asucrose molecule nominally esterified preferably with two acetic acidand six isobutyric acid moieties, is used as the HVLCM.

SAIB is orally non-toxic and is currently used as to stabilize emulsionsin the food industry. It is a very viscous liquid and has an unusualproperty that there is a dramatic change in viscosity with smalladditions of heat or with the addition of solvents. It is soluble in alarge number of biocompatible solvents. When in solution or in anemulsion, SAIB can be applied via injection or an aerosol spray. SAIB iscompatible with cellulose esters and other polymers that can affect therate of delivery of the substance.

In other embodiments, the HVLCM can be stearate esters such as those ofpropylene glycol, glyceryl, diethylaminoethyl, and glycol, stearateamides and other long-chain fatty acid amides, such as N,N′-ethylenedistearamide, stearamide MEA and DEA, ethylene bistearamide, cocoamineoxide, long-chain fatty alcohols, such as cetyl alcohol and stearylalcohol, long-chain esters such as myristyl myristate, beheny erucate,and glyceryl phosphates. In a particular embodiment, the HVLCM isacetylated sucrose distearate (Crodesta A-10). Additional materialssuitable for use as the HVLCM are disclosed in US Patent ApplicationPublication US 2004/0101557 by Gibson et al.

The amount of HVLCM in a formulation will depend on the desiredproperties of a formulation and the solvent capacity of the chosensolvent. If the chosen solvent has poor solvent capacity performance,then the actual amount of solvent may be large, with a correspondingreduction in the amount of HVLCM in the formulation. The HVLCM istypically present in controlled delivery compositions in an amount inthe range from about 99.5 percent to about 10 percent by weight, moretypically, between 95 and 25 percent, and most typically, between 85 and45, relative to the total weight of the composition.

“Polymer” means a naturally occurring or synthetic compound made up of alinked series of repeat units. Polymer(s) include, but are not limitedto, thermoplastic polymers and thermoset polymers. Polymer(s) maycomprise linear polymers and/or branched polymers. Polymers may besynthesized from a single species of monomers, or may be copolymers thatmay be synthesized from more than one species of monomers. Inembodiments, polymers according to the invention comprise polymers thatcomprise lactide repeat units. Polymers according to the invention mayalso comprise repeat units of other suitable materials, including butnot limited to glycolide repeat units, polyethylene glycol repeat units,caprolactone repeat units, valerolactone repeat units, and the like.Initiators for such polymers include but are not limited to diolinitiators including 1,6-hexanediol, 1,2-propanediol, 1,3-propanediol,1,4-butanediol and the like; diol initiators including difunctionalpoly(ethylene glycol)s (PEGs); monofunctional alcohol initiatorsincluding 1-dodecanol, methyl lactate, ethyl lactate and the like;monofunctional PEGs including methoxy(polyethylene glycol) (mPEG); andother initiators including water, glycolic acid, lactic acid, citricacid, and the like. In preferred embodiments, the polymer comprises abiodegradable polymer. In additional preferred embodiments, the polymercomprises a biocompatible polymer. In embodiments, the polymer may bepresent in amounts ranging from about 1 wt % to about 45 wt %; morepreferably, the polymer may be present in amounts ranging from about 5wt % to about 35 wt %; and yet more preferably the polymer may bepresent in amounts ranging from about 5 wt % to about 25 wt %, all basedon the total weight of the formulation. In other embodiments, thepolymer may be present in an amount ranging from about 15 wt % to about45 wt %; preferably the polymer may be present in amounts ranging fromabout 15 wt % to about 35 wt %, all based on the total weight of theformulation.

“Repeat units” means residues of monomers that are covalentlyincorporated into a polymer. In embodiments, lactide repeat unitscomprise lactide residues. In certain embodiments, glycolide repeatunits comprise glycolide residues. In embodiments, a linear polymer maypossess a ratio R of lactide repeat units to total repeat units in thelinear polymer, wherein R may range from about 0.55 to about 0.95.Ranges of R of particular interest are from about 0.55 to 0.85, and fromgreat than 0.85 to about 0.95. R may be determined experimentally oranalytically for each polymer by proton NMR or similar techniques.

“Solvent(s) means materials that are capable of dissolving othermaterials. Preferably, solvents used in the practice of the presentinvention are biocompatible, water miscible and/or water soluble, and/ornon-toxic. In embodiments, the biologically active substance may besoluble in the solvent. The solvents used to inject the inventiveformulations into animals should not cause significant tissue irritationor necrosis at the site of implantation, unless irritation or necrosisis the desired effect.

The solvent is preferably water miscible and/or water soluble, so thatit will diffuse into bodily fluids or other aqueous environment, causingthe formulation to assume a more viscous form. Certain solvents that arenot water miscible and/or not water soluble may also be used in thepractice of the invention. Examples of suitable solvents include but arenot limited to ethanol, ethyl lactate, propylene carbonate, glycofurol,N-methylpyrrolidone, 2-pyrrolidone, benzyl benzoate, miglyol, propyleneglycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,benzyl alcohol, triacetin, dimethylformamide, dimethylsulfoxide,tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and/or1-dodecylazacycloheptan-2-one, and combinations of any of the above;with the proviso that one or more of the above listed solvents may bespecifically excluded from the scope of the invention if it is to bedisclaimed.

When SAIB is used as the HVLCM, the preferred solvents include ethanol,dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol,triacetin, N-methylpyrrolidone, propylene carbonate, and glycofurol.SAIB is not miscible with glycerol, corn oil, peanut oil,1,2-propanediol, polyethylene glycol (PEG200), super refined sesame oil,and super refined peanut oil. Accordingly, the latter group of solventsare not preferred for use with SAIB.

“Solvent capacity” means amount(s) of the one or more solvents thatdissolves the HVLCM and linear polymer in the formulation to the sameextent as would a hypothetical amount of N-methylpyrrolidone in theformulation. Solvent capacity is expressed as that hypothetical weightpercent of N-methylpyrrolidone in the formulation, based on the totalweight of the hypothetical formulation that would contain theN-methylpyrrolidone.

Thus, in an embodiment, a formulation having a solvent capacity of about20% would have sufficient amounts of one or more solvents to dissolvethe HVLCM and linear polymer to the same extent as if about 20% byweight of NMP were added to the formulation instead of the one or moresolvents. If NMP were present as the one or more solvents in thisembodiment, it would be present in an amount of about 20% by weight,based on the total weight of the formulation. If the one or moresolvents were poorer solvents for the HVLCM and linear polymer, then theone or more solvents would be present in an amount greater than about20% by weight, based on the total weight of the formulation. This isillustrated further in Examples 10 and 11.

In certain embodiments, when R (the ratio of lactide repeat units tototal repeat units in the linear polymer) is between about 0.55 to 0.85,the solvent capacity of the one or more solvents is greater than orequal to about 35%, more preferably greater than or equal to about 25%;and still more preferably greater than or equal to about 20%. Likewise,in certain embodiments, when R ranges from greater than 0.85 to about0.95, the solvent capacity of the one or more solvents is greater thanor equal to about 25%, more preferably greater than or equal to about15%, and still more preferably greater than or equal to about 10%.Decrease in the lower boundary of solvent capacities represents aphysical narrowing of the range of claimed formulations. This is becausethe number of formulations that exhibit satisfactory solubility behaviorover the full range of recited solvent capacities decreases as the lowerboundary of solvent capacity decreases.

“Subject” is used interchangeably with “individual” and means any humanor animal with which it is desired to practice the present invention.The term “subject” does not denote a particular age, and the presentsystems are thus suited for use with subjects of any age, such asinfant, adolescent, adult and senior aged subjects In certainembodiments, a subject may comprise a patient.

“Weight average molecular weight” or “Mw” means the weighted averagemolecular weight of polymers of interest. It can be expressed at thefirst moment of a plot of the weight of polymer in each molecular weightrange against molecular weight. In certain embodiments, weight-averagemolecular weight, Number-average molecular weight (Mn), and themolecular weight distribution (MWD=Mw/Mn) may be measured by gelpermeation chromatography (GPC). GPC is a column fractionation methodwherein polymer molecules in solutions are separated based on theirsizes. The separated polymer molecules are observed by a detector togenerate the GPC chromatogram, which is a plot of elution volume or time(related to molecular size) versus abundance. The GPC chromatogram maybe integrated to determine Mw, Mn, and MWD.

GPC samples of polymer(s) of interest, approximately 50 mg in 10 mLsolvent, are filtered through a 0.2 μm Teflon filter before injectioninto the instrument. Injections of 50-200 μL are made to generatechromatograms. Chromatograms may be generated using various systems. Inan embodiment, a system comprises an Agilent LC 1100 using Chemstationsoftware. In another embodiment, a system comprises a Waters 510 pump, aShimadzu CTO-10A column oven, and a Waters 410 differentialrefractometer. Data may be recorded directly to a PC via a Polymer Labsdata capture unit using Caliber® software. A calibration curve may begenerated using polystyrene standards. Mw, Mn, and MWD relative topolystyrene are calculated. Preferred solvents for use in GPC comprise:chloroform, dichlormethane (methylene chloride), and tetrahydrofuran(THF). Preferred different column sets comprise: (1) two Polymer LabsMixed C columns in series, (2) two Polymer Labs Mixed D columns inseries, or (3) two Polymer Labs Mesopore columns in series. Preferredpolystyrene calibrants comprise: Polymer Labs Easical PS1 kit, PolymerLabs Easical PS2 kit, Polymer Labs S-L-10 kit.

In embodiments, the weight average molecular weight of polymers usefulin the practice of the present invention is less than or equal to about15,000 Daltons, additionally more preferably less than or equal to about12,500 Daltons, and yet more preferably less than or equal to about10,000 Daltons.

Formulations

As noted above, an important consideration in development offormulations according to the invention is the miscibility or solubilityof the polymer in the formulation with the HVLCM. In situations wherethe polymer is not miscible or soluble in the formulation with theHVLCM, phase separation of the polymer and the HVLCM in the formulationmay occur. Once this occurs, it may be very difficult to remix thepolymer and the HVLCM, especially at the point of use. Should improperremixing occur, undesirably wide variations in release performance mightresult. Accordingly, formulations that have high miscibility orsolubility of the polymer in the formulation with the HVLCM aredesirable.

The inventive formulations possess this high miscibility or solubilityof the polymer in the formulation with the HVLCM. Other points useful toconsider in terms of formulation strategy may include the following.Minimizing total solvent content of the formulations is generallybiologically desirable, for instance in an embodiment having a solventcontent ranging from about one weight percent up to about 35 wt %solvent, preferably ranging from about one weight percent up to about 30wt %, and yet more preferably ranging from about one weight percent upto about 25 wt %, based on the total weight of the formulation. Incontrast, increasing solvent content can move a HVLCM/linearpolymer/solvent composition from phase separation to single phasebehavior. The one or more solvents should be biocompatible, which mayeliminate some solvents from use in the invention. In an embodiment, theone or more solvents should be good solvents for both the polymer andHVLCM. In an alternate embodiment, the formulation may comprise theHVLCM, the linear polymer, one or more good solvents for the linearpolymer and one or more good solvents for the HVLCM, with the resultantformulation being a single phase.

Solubility and phase separation of various HVLVM/linear polymer/solventformulation may be investigated by visual techniques well known to thoseskilled in the art. For formulations with significant instability ortendency to phase-separate, the linear polymer may absorb solvent butremain as a separated, very viscous layer or phase in the formulation.Other formulations might be rendered into a uniform clear solution bysufficient heating and mixing. However, when cooled to room temperature,two clear liquid phases may form. Sometimes, the two clear layers maynot be easy to detect, thus requiring strong light and a thoroughinspection of the formulation to discern the boundary between the twophases. In a number of cases, formulations may appear clear and uniformon initial cooling to room temperature, but when left quiescent at roomtemperature for a period of several days or greater, the formulationsmay separate into two phases. For formulations that are at the border ofphase separation, the formulation may turn cloudy and sometimes slowlyseparate into two phases.

A variety of additives can optionally be included in the inventiveformulations to modify the properties of the formulations as desired.The additives can be present in any amount that is sufficient to impartthe desired properties to the formulations. The amount of additive usedwill in general be a function of the nature of the additive and theeffect to be achieved, and can be easily determined by one of skill inthe art.

When present, additive(s) are typically present in the formulations inan amount in the range from about 0.1 percent to about 20 percent byweight, relative to the total weight of the formulation, and moretypically, is present in the composition in an amount in the range fromabout 1, 2, or 5 percent to about 10 percent by weight, relative to thetotal weight of the formulation. Certain additives, such as buffers, maybe present only in small amounts in the relative to the total weight ofthe formulation.

Another additive for use with the present compositions arenon-biodegradable polymers. Non-limiting examples of non-erodiblepolymers which can be used as additives include: polyacrylates,ethylene-vinyl acetate polymers, cellulose and cellulose derivatives,acyl substituted cellulose acetates and derivatives thereof,non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinylfluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, andpolyethylene oxide.

Preferred non-biodegradable polymers include polyethylene, polyvinylpyrrolidone, ethylene vinylacetate, polyethylene glycol, celluloseacetate butyrate (“CAB”) and cellulose acetate propionate (“CAP”).

A further class of additives which can be used in the inventiveformulations are natural and synthetic oils and fats. Oils derived fromanimals or from plant seeds of nuts typically include glycerides of thefatty acids, chiefly oleic, palmitic, stearic, and linolenic. As a rulethe more hydrogen the molecule contains, the thicker the oil becomes.

Non-limiting examples of suitable natural and synthetic oils includevegetable oil, peanut oil, medium chain triglycerides, soybean oil,almond oil, olive oil, sesame oil, peanut oil, fennel oil, camellia oil,corn oil, castor oil, cotton seed oil, and soybean oil, either crude orrefined, and medium chain fatty acid triglycerides.

Fats are typically glyceryl esters of higher fatty acids such as stearicand palmitic. Such esters and their mixtures are solids at roomtemperatures and exhibit crystalline structure. Lard and tallow areexamples. In general oils and fats increase the hydrophobicity of theformulation, slowing degradation and water uptake.

Another class of additives which can be used in the inventiveformulations comprise carbohydrates and carbohydrate derivatives.Non-limiting examples of these compounds include monosaccarides (simplesugars such as fructose and its isomer glucose (dextrose); disaccharidessuch as sucrose, maltose, cellobiose, and lactose; and polysaccarides.

Other additives, such as preservatives, stabilizers, anti-oxidants,coloring agents, isotonic agents, humectants, sequesterants, vitaminsand vitamin precursors, surfactants and the like, may be added asneeded. As preferred examples of preservatives, paraben derivatives aregiven with methyl paraben and propyl paraben given as most preferredpreservatives. As preferred examples of anti-oxidants, butylhydroxyanisole, butyl hydroxytoluene, propyl gallate, vitamin E acetate,and purified hydroquinone are given with vitamin E acetate and butylhydroxytoluene given as most preferred anti-oxidants. Given as preferredexamples of humectant is sorbitol. Given as preferred examples ofsequesterant is citric acid.

Inventive formulations may be made according to a number of methods. Incertain embodiments, first combine room temperature solvent(s), roomtemperature linear polymer and HVLCM heated to 80° C. Next, mix at60-80° C. for a period of several hours to overnight (8-16 hours) untilthe formulation is well-mixed. In other embodiments, dissolve the linearpolymer in all of the solvent(s). Add hot HVLCM (heated at up to 80°C.). Then, mix at temperature of room temperature to 80° C. for 1 hourto overnight (8-16 hours) until the formulation is well-mixed. In yetother embodiments, dissolve the linear polymer in some of thesolvent(s). Mix the remainder of the solvent(s) with the HVLCM. Add hotHVLCM/solvent mixture (heated at up to 80° C.) to the linearpolymer/solvent(s) mixture. Then, mix at temperatures that may rangefrom room temperature to 80° C. for 1 hour to overnight (8-16 hours),until the formulation is well-mixed.

Inventive formulations are preferably prepared at temperatures aboveroom temperature. Once mixed, the formulations may be cooled back toroom temperature and initially observed for cloudiness (indication ofincipient phase separation), the presence of two liquid layers (usuallyof low to moderate viscosity) or the presence of a viscous layerunderneath a less viscous layer. The formulations may then be left atroom temperature for a significant period (usually one week or greater)and observed again for cloudiness, separation into two layers ofmoderate viscosity or the presence of a viscous layer.

Inventive formulations may be administered to subjects usingconventional routes of administration, such as injection. Effectiveamounts of biologically active substances may be incorporated into theinventive formulations so as to achieve a desired pharmacologicaleffect.

While there has been described and pointed out features and advantagesof the invention, as applied to present embodiments, those skilled inthe medical art will appreciate that various modifications, changes,additions, and omissions in the method described in the specificationcan be made without departing from the spirit of the invention.

The present invention is not to be limited in terms of the particularembodiments described in this application, which are intended as singleillustrations of individual aspects of the invention. Many modificationsand variations of this invention can be made without departing from itsspirit and scope, as will be apparent to those skilled in the art.Functionally equivalent methods within the scope of the invention, inaddition to those enumerated herein, will be apparent to those skilledin the art from the foregoing description. Such modifications andvariations are intended to fall within the scope of the appended claims.The present invention is to be limited only by the terms of the appendedclaims, along with the full scope of equivalents to which such claimsare entitled.

The following Examples are meant to be illustrative of the claimedinvention, and not limiting in any way.

EXAMPLES Example 1: Formulation Examples

Various formulation examples according to the invention, together withvarious comparative formulation examples, were prepared. Informationrelating to these examples is set forth in Table 1. The polymersynthesis, and formulation techniques for several representativeexamples have been set forth below. The remaining non-representativeexamples were prepared using such representative techniques, and withconventionally obtainable modifications to the representativetechniques.

Example 2

A 500 mL three-neck round bottom flask, a glass stirrer bearing, a gasjoint, and a glass stirring shaft were dried in a glassware oven at 100°C. to remove all traces of moisture. The following materials weretransferred to the flask: 179.00 g DL-lactide, 71.00 g of glycolide, and13.75 g 1,6-hexanediol. The flask was equipped with the stirring shaftwith a Teflon paddle, the stirrer bearing, and a gas joint connected toa manifold with vacuum and nitrogen gas supply. The stirrershaft/bearing was sealed with a rubber balloon and the reaction mixturewas evacuated for several minutes and the flask was backfilled withnitrogen gas. The flask was immersed in an oil bath maintained at 150°C. and stirred using an overhead stirrer attached to the shaft/paddleassembly. Once all of the monomer had melted, a charge of stannous2-ethylhexanoate was added, 0.075 g in a solution of toluene (559 mL ofa solution with a concentration of 0.13416 g/mL) was added to the melt.Stirring was continued for 4 hours Next, the temperature of the oil bathwas reduced to 115° C., stirring was stopped, and the stirrershaft/bearing was sealed with a rubber balloon and the reaction mixturewas evacuated under full vacuum for 1 hour. The polymer was then pouredonto a piece of Teflon film in a glass dish and allowed to cool. Thefinished polymer was stored protected from ambient moisture in a vacuumoven and/or plastic bags. The resulting polymer had a Mw of 5300 Da asdetermined approximately by GPC, and an R ratio of 0.65.

Example 3: Formulation 6

PLGA polymer produced according to Example 2 was removed from coldstorage & allowed to warm to room temperature. SAIB (in a glass jar) washeated to 80° C. for several hours. 5.69 grams of hot SAIB were pouredinto a glass jar. Next, 2.59 grams of NMP were dispensed into the glassjar. Next, 2.05 grams of 65/35 PLGA polymer were dispensed into theglass jar. The jar was sealed and fastened to a rotating mixing wheel.The mixing wheel was placed into an 80° C. oven and turned on so thatthe jar rotated at the outside of a circular path at a rate sufficientto achieve mixing. After two hours of mixing at 80° C., the jar wasremoved from the mixing wheel and allowed to cool to room temperature.The formulation composition was 55% SAIB, 25% NMP and 20% PLGA. Onstanding, the formulation remained clear and did not exhibit anyevidence of phase separation.

Example 4

A 1 L three-neck round bottom flask, a glass stirrer bearing, a gasjoint, and a stirring shaft were dried in a glassware oven at 100° C. toremove all traces of moisture. The following materials were transferredto the flask: 179.00 g DL-lactide, 71.00 g of glycolide, and 2.1 g ofwater. The flask was equipped with a stirring shaft and a Teflon paddle,a stirrer bearing, and a gas joint connected to a manifold with vacuumand nitrogen gas supply. The stirrer shaft/bearing was sealed and thereaction mixture was evacuated for several minutes and the flask wasbackfilled with nitrogen gas. This was repeated 4 additional times. Theflask was immersed in an oil bath maintained at 159° C. and stirredusing an overhead stirrer attached to the shaft/paddle assembly. Onceall of the monomer had melted, a charge of stannous 2-ethylhexanoate,0.1125 g in a solution of toluene, was added to the melt. Stirring wascontinued for 15 hours. Next, the temperature of the oil bath wasreduced to 115° C., stirring was stopped, and the stirrer shaft/bearingwas sealed and the reaction mixture was evacuated under full vacuum for1 hour. The polymer was then poured onto a piece of Teflon film in aglass dish and allowed to cool. The finished polymer was storedprotected from ambient moisture in a vacuum oven and/or plastic bags.The resulting polymer had a Mw of 7200 Da as determined approximately byGPC, and an R ratio of 0.65.

Example 5: Comparative Formulation C3

3.28 grams of PLGA polymer made according to Example 4 were dissolved ina mixture of 1.55 grams of DMSO and 1.55 grams of ethanol. 24.98 gramsof warm SAIB were added, with a resulting nominal formulation of 10.5%PLGA, 4.9% DMSO, 4.9% ethanol and 79.7% SAIB. The formulation separatedinto two phases at room temperature. Additional DMSO (3.90 grams) andadditional ethanol (2.25 grams) were added to yield a nominalformulation of 8.8% PLGA, 14.5% DMSO, 10.1% ethanol and 66.6% SAIB. Theformulation remained separated into two phases.

Example 6: Formulation 6 (Alternate Formulation Methodology)

PLGA polymer produced according to Example 2 was removed from coldstorage & allowed to warm to room temperature. 20.36 grams of 65/35 PLGApolymer were dispensed into a glass jar. 25.45 grams of NMP were addedto the jar and the jar was sealed. The jar was fastened to a rotatingmixing wheel (Glas Col, Terre Haute, Ind.). The mixing wheel was turnedon so that the jar rotated at the outside of a circular path, withheating at approximately 80 C until the polymer was dissolved in theNMP. 55.49 grams of SAIB (warmed) were added to the polymer/NMPsolution. The jar was sealed and fastened to a rotating mixing wheel(Glas Col, Terre Haute, Ind.). The mixing wheel was turned on so thatthe jar rotated at the outside of a circular path at a speed sufficientto achieve mixing. The solution was mixed until a uniform preparationwas achieved. The formulation composition was 55% SAIB, 25% NMP and 20%PLGA, all expressed as wt % based on total weight of the formulation. Onstanding, the vehicle remained clear and did not exhibit any evidence ofphase separation.

Example 7: Solvent Capacity Experiments

Approximately 2.5 g of PLGA having a molecular weight of 4700 Da, alactide/glycolide ratio of 65/35, and initiated by hexanediol; and 6.855g of SAIB were added to a vial (i.e. fixed weight relationship ofpolymer to SAIB). Solvents, as shown in Table 2 below, were slowly addedand the formulation was mixed at 60° C. in a Emprotech Unitherm® ovenuntil a single phase solution was formed. The solution was then removedfrom the oven and allowed to sit on a bench top at roughly roomtemperature for approximately a week. If the solution phase separatedmore solvent was added and the formulation was mixed at 60° C. until asingle phase solution was formed and remained a single phase for oneweek while sitting on the bench top at roughly room temperature. Thefinal compositions are shown in Table as shown in Table 2 below. Thesolvent capacity of this vehicle was 25.61 wt %. 26.44 wt % wt % of BAor 42.64 wt % of DMSO were needed to achieve that solvent capacity.

TABLE 2 (figures are weight percent of total final weight) MaterialTrial A Trial B Trial C SAIB 53.86 41.99 54.55 PLGA 19.70 15.37 19.84NMP 25.61 BA 26.44 DMSO 42.64

Example 8: Solvent Capacity Experiments

Approximately 2.5 g of PLGA having a molecular weight of 6600 Da, alactide/glycolide ratio of 65/35, and initiated with dodecanol; and6.855 g of SAIB were added to a vial. Solvents, as shown in Table 3below, were slowly added and the formulation was mixed at 60° C. in aEmprotech Unitherm® oven until a single phase solution was formed. Thesolution was then removed from the oven and allowed to sit on a benchtop at roughly room temperature for approximately a week. If thesolution phase separated more solvent was added and the formulation wasmixed at 60° C. until a single phase solution was formed and remained asingle phase for one week while sitting on the bench top at roughly roomtemperature. The final compositions are shown in Table 3 below. Thesolvent capacity of this vehicle was 17.36 wt %. 19.70 wt % of BA or31.22 wt % of DMSO were needed to achieve that solvent capacity.

TABLE 3 (Figures are weight percent of total final weight) MaterialTrial D Trial E Trial F SAIB 58.83 50.37 60.58 PLGA 21.47 18.41 22.06NMP 17.36 BA 19.70 DMSO 31.22

Example 9: Naltrexone Formulation

0.555 grams of PLGA (65/35 LG, 1-dodecanol initiated, MW of 6400 Daltonsby GPC, from DURECT® Birmingham) was mixed with 3.620 grams of BenzylAlcohol (from J.T.Baker) in a sealed bottle by gentle inversion inside aLindberg/Blue M oven at 60° C. for 35 minutes, resulting in homogeneoussolution. To this mixture was added 6.094 grams of hot SAIB (fromEastman Chemicals). The vehicle was mixed by gentle inversion forapproximately 65 hours at room temperature. A uniform vehicle resulted(SAIB/benzyl alcohol/PLGA 59.34/35.25/5.40). 0.118 grams of naltrexonebase (Mallinckrodt) was added to a separate bottle. 4.205 grams of thevehicle was added to this bottle. The naltrexone was dissolved in thevehicle by gentle inversion for approximately 3 hours, resulting in auniform clear solution that was pale yellow in color. The composition ofthe naltrexone formulation (in wt % based on total formulation weight)was:

PLGA: 5.3% Benzyl alcohol 34.3% SAIB 57.7% Naltrexone 2.7%

Example 10: Risperidone Formulation

The atypical antipsychotic drug risperidone was added to the formulationof Example 3 (Formulation 26) as follows:

To 7.33 grams of Formulation 26, 1.095 grams of risperidone (fromKemprotec) were added. The vial was placed on a Glas-Col rotating wheelset at 30% for approximately two hours until a homogeneous suspensionwas obtained. The resulting formulation had the composition of 48% SAIB,22% NMP, 17% PLGA and 13% Risperidone, with percentages expressed asweight percent based on total weight of the formulation. The resultingvehicle was a stable homogeneous suspension.

TABLE 1 Mw Formulation #: Polymer R (GPC) Formulation compositionSolubility Behavior 1 PLGA 65/35- 0.65 7200 SAIB/NMP/EtOH/PLGA-COOH:Soluble COOH 68.4/13.2/9.2/9.3 2 PLGA 65/35 0.65 5300 SAIB/NMP/PLGA:70/25/5 Soluble 3 PLGA 65/35 0.65 5300 SAIB/NMP/PLGA: 70.3/20.3/9.4Soluble 4 PLGA 65/35 0.65 5300 SAIB/NMP/PLGA: 59.7/26.5/13.8 Soluble 5PLGA 65/35 0.65 5300 SAIB/NMP/PLGA: 65/30/15 Soluble 6 PLGA 65/35 0.655300 SAIB/NMP/PLGA: 55/25/20 Soluble 7 PLGA 65/35 0.65 5300SAIB/NMP/EtOH/PLGA: 58.6/14.0/9.4/18.0 cloudy but single phase 8 PLGA65/35 0.65 5300 SAIB/NMP/EtOH/PLGA: Soluble 55.0/15.1/10.0/20.0 9 PLGA65/35 0.65 5300 SAIB/NMP/EtOH/PLGA: 55.1/19.9/5.0/20.0 Soluble 10 PLGA65/35 0.65 5300 SAIB/NMP/DMSO/PLGA: Soluble 54.1/19.8/6.0/20.1 11 PLGA65/35 0.65 5300 SAIB/NMP/BA/PLGA: 55/20/5/20 Soluble 12 PLGA 65/35 0.655300 SAIB/DMSO/EtOH/PLGA: 65/25/5/5 Soluble 13 PLGA 65/35 0.65 5300SAIB/DMSO/BA/PLGA: 65/25/5/5 Soluble 14 PLGA 65/35 0.65 5300SAIB/DMSO/NMP/PLGA: 65/25/5/5 Soluble 15 PLGA 65/35 0.65 4100SAIB/NMP/PLGA: 53.1/21.9/25.0 Soluble 16 PLGA 65/35 0.65 4100SAIB/NMP/PLGA: 49.2/22.6/28.2 Soluble 17 PLGA 65/35 0.65 4100SAIB/NMP/PLGA: 29.7/33.9/36.4 Soluble 18 PLGA 65/35 0.65 3200SAIB/NMP/PLGA: 70.0/20.0/10.0 Soluble 19 PLGA 65/35 0.65 4700SAIB/NMP/PLGA: 55/25/20 Soluble 20 PLGA 65/35 0.65 6600 SAIB/NMP/PLGA:55/25/20 Soluble 21 PLGA 65/35 0.65 6600 SAIB/NMP/EtOH/PLGA: 55/15/10/20Soluble 22 PLGA 60/40 0.6 3200 SAIB/NMP/PLGA: 70.0/20.0/10.0 Soluble 23PLGA 55/45 0.55 3200 SAIB/NMP/PLGA: 65/25/10 Soluble C1 PLGA 0.65 7200SAIB/NMP/PLGA-COOH: 70/25/5 not soluble 65/35- COOH C2 PLGA 0.65 7200SAIB/BA/EtOH/PLGA-COOH: not soluble 65/35- 65.3/14.1/11.1/9.5 COOH C3PLGA 0.65 7200 SAIB/DMSO/EtOH/PLGA: not soluble 65/35-66.6/14.5/10.1/8.8 COOH C4 PLGA 65/35 0.65 5300 SAIB/NMP/PLGA: 75/15/10not soluble C5 PLGA 65/35 0.65 5300 SAIB/NMP/PLGA: 65/20/15 not solubleC6 PLGA 65/35 0.65 5300 SAIB/NMP/PLGA: 60/20/20 not soluble C7 PLGA65/35 0.65 5300 SAIB/NMP/EtOH/PLGA: 72.9/8.8/8.6/9.6 not soluble C8 PLGA65/35 0.65 5300 SAIB/NMP/EtOH/PLGA: 62.0/17.2/4.6/16.2 separates longterm C9 PLGA 65/35 0.65 5300 SAIB/NMP/DMSO/PLGA: separates long term53.8/15.4/10.8/20.1 C10 PLGA 65/35 0.65 5300 SAIB/NMP/DMSO/PLGA:separates long term 54.9/15.0/9.8/20.1 C11 PLGA 65/35 0.65 5300SAIB/NMP/DMSO/PLGA: 55/20/5/20 separates long term C12 PLGA 65/35 0.655300 SAIB/NMP/BB/PLGA: 55/20/5/20 not soluble C13 PLGA 65/35 0.65 5300SAIB/DMSO/PLGA: 70/25/5 not soluble C14 PLGA 65/35 0.65 5300SAIB/DMSO/PLGA: 65/30/5 not soluble C15 PLGA 65/35 0.65 5300SAIB/DMSO/EtOH/PLGA: 71.7/10.0/8.7/9.7 not soluble C16 PLGA 65/35 0.655300 SAIB/DMSO/BB/PLGA: 65/25/5/5 not soluble C17 PLGA 65/35 0.65 5300SAIB/BA/EtOH/PLGA: 69.8/11.8/8.8/9.5 not soluble C18 PLGA 0.50 5500SAIB/NMP/PLGA-COOH: 70/25/5 separates at RT & 37 C. 50/50- COOH

1.-40. (canceled)
 41. A formulation comprising: a biologically activesubstance; and a vehicle comprising: (i) sucrose acetate isobutyrate(SAIB) in an amount of from 25 to 85 wt % based on total weight of thevehicle; (ii) a linear poly(lactide-co-glycolide) in an amount of from10 to 45 wt % based on total weight of the vehicle, wherein the linearpoly(lactide-co-glycolide) possesses a ratio R of lactide repeat unitsto total repeat units in the linear poly(lactide-co-glycolide); and(iii) one or more solvents that have a solvent capacity, wherein the oneor more solvents dissolve the SAIB and the linearpoly(lactide-co-glycolide), and wherein the SAIB, linearpoly(lactide-co-glycolide), and one or more solvents are monophasic whenmaintained at approximately 25° C. for a one-week period; wherein thelinear poly(lactide-co-glycolide) has a weight average molecular weightless than or equal to 15 kilodaltons, and wherein (a) R satisfies thefollowing: 0.55≤R≤about 0.95; (b) when R satisfies the following:0.55≤R≤0.85, the solvent capacity of the one or more solvents is greaterthan or equal to 25%; and (c) when R satisfies the following: greaterthan 0.85 to about 0.95, the solvent capacity of the one or moresolvents is greater than or equal to about 10%.
 42. The formulation ofclaim 41, wherein the biologically active substance comprises anatypical antipsychotic.
 43. The formulation of claim 41, wherein thebiologically active substance comprises an antiviral.
 44. Theformulation of claim 41, wherein the linear poly(lactide-co-glycolide)is present in an amount ranging from about 15 wt % to 45 wt %, based onthe total weight of the vehicle.
 45. The formulation of claim 41,wherein the linear poly(lactide-co-glycolide) has a weight averagemolecular weight less than 12.5 kilodaltons.
 46. The formulation ofclaim 41, wherein when R satisfies the following: greater than 0.85 toabout 0.95, the solvent capacity of the one or more solvents is greaterthan or equal to about 15%.
 47. The formulation of claim 41, whereinwhen R satisfies the following: greater than 0.85 to about 0.95, thesolvent capacity of the one or more solvents is greater than 20%.
 48. Amethod of administering a biologically active substance comprisingadministering the formulation of claim
 41. 49. A formulation comprising:a biologically active substance; and a vehicle comprising: (i) sucroseacetate isobutyrate (SAIB) in an amount of from 25 to 85 wt % based ontotal weight of the vehicle; (ii) a linear poly(lactide-co-glycolide) inan amount of from 10 to 45 wt % based on total weight of the vehicle,wherein the linear poly(lactide-co-glycolide) possesses a ratio R oflactide repeat units to total repeat units in the linearpoly(lactide-co-glycolide); and (iii) one or more solvents that have asolvent capacity, wherein the one or more solvents dissolve the SAIB andthe linear poly(lactide-co-glycolide), and wherein the SAIB, linearpoly(lactide-co-glycolide), and one or more solvents are monophasic whenmaintained at approximately 25° C. for a one-week period; wherein thelinear poly(lactide-co-glycolide) has a weight average molecular weightless than or equal to 15 kilodaltons, and wherein: (a) R satisfies thefollowing: 0.55≤R≤0.85; and (b) the solvent capacity of the one or moresolvents is greater than or equal to 25%.
 50. The formulation of claim49, wherein the biologically active substance comprises an atypicalantipsychotic.
 51. The formulation of claim 49, wherein the biologicallyactive substance comprises an antiviral.
 52. The formulation of claim49, wherein the linear poly(lactide-co-glycolide) is present in anamount ranging from about 15 wt % to 45 wt %, based on the total weightof the vehicle.
 53. The formulation of claim 49, wherein the linearpoly(lactide-co-glycolide) has a weight average molecular weight lessthan 12.5 kilodaltons.
 54. A method of administering a biologicallyactive substance comprising administering the formulation of claim 49.55. A formulation comprising: a biologically active substance; and avehicle comprising: (i) sucrose acetate isobutyrate (SAIB) in an amountof from 25 to 85 wt % based on total weight of the vehicle; (ii) alinear poly(lactide-co-glycolide) in an amount of from 10 to 45 wt %based on total weight of the vehicle, wherein the linearpoly(lactide-co-glycolide) possesses a ratio R of lactide repeat unitsto total repeat units in the linear poly(lactide-co-glycolide); and(iii) one or more solvents that have a solvent capacity, wherein the oneor more solvents dissolve the SAIB and the linearpoly(lactide-co-glycolide), and wherein the SAIB, linearpoly(lactide-co-glycolide), and one or more solvents are monophasic whenmaintained at approximately 25° C. for a one-week period; wherein thelinear poly(lactide-co-glycolide) has a weight average molecular weightless than or equal to 15 kilodaltons, and wherein R satisfies thefollowing: greater than 0.85 to about 0.95; and the solvent capacity ofthe one or more solvents is greater than or equal to about 10%.
 56. Theformulation of claim 55, wherein the biologically active substancecomprises an atypical antipsychotic.
 57. The formulation of claim 55,wherein the biologically active substance comprises an antiviral. 58.The formulation of claim 55, wherein the linearpoly(lactide-co-glycolide) is present in an amount ranging from about 15wt % to 45 wt %, based on the total weight of the vehicle.
 59. Theformulation of claim 55, wherein the linear poly(lactide-co-glycolide)has a weight average molecular weight less than 12.5 kilodaltons. 60.The formulation of claim 55, wherein the solvent capacity of the one ormore solvents is greater than or equal to about 15%.
 61. The formulationof claim 55, wherein the solvent capacity is greater than 20%.
 62. Theformulation of claim 55, wherein the solvent capacity of the one or moresolvents is greater than or equal to about 25%.
 63. A method ofadministering a biologically active substance comprising administeringthe formulation of claim
 55. 64. A formulation comprising: abiologically active substance; and a vehicle comprising: (i) sucroseacetate isobutyrate (SAIB) in an amount of from 25 to 85 wt % based ontotal weight of the vehicle; (ii) a linear poly(lactide-co-glycolide) inan amount of from 10 to 45 wt % based on total weight of the vehicle,wherein the linear poly(lactide-co-glycolide) possesses a ratio R oflactide repeat units to total repeat units in the linearpoly(lactide-co-glycolide), wherein R satisfies the following:0.55≤R≤about 0.95; and (iii) one or more solvents present in an amountranging from 25 weight percent up to about 43 weight percent, based ontotal weight of the vehicle, wherein the one or more solvents dissolvethe SAIB and the linear poly(lactide-co-glycolide), and wherein theSAIB, linear poly(lactide-co-glycolide), and one or more solvents aremonophasic when maintained at approximately 25° C. for a one-weekperiod; wherein the linear poly(lactide-co-glycolide) has a weightaverage molecular weight less than or equal to 15 kilodaltons, andwherein the one or more solvents comprise ethanol, ethyl lactate,propylene carbonate, glycofurol, N-methylpyrrolidone, 2-pyrrolidone,benzyl benzoate, caprylic/capric triglyceride, propylene glycol,acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, benzylalcohol, triacetin, dimethylformamide, dimethylsulfoxide,tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid,1-dodecylazacycloheptan-2-one, and combinations thereof.
 65. Theformulation of claim 64, wherein the biologically active substancecomprises an atypical antipsychotic.
 66. The formulation of claim 64,wherein the biologically active substance comprises an antiviral. 67.The formulation of claim 64, wherein the linearpoly(lactide-co-glycolide) is present in an amount ranging from about 15wt % to 45 wt %, based on the total weight of the vehicle.
 68. Theformulation of claim 64, wherein the linear poly(lactide-co-glycolide)has a weight average molecular weight less than 12.5 kilodaltons. 69.The formulation of claim 64, wherein the one or more solvents is presentin an amount ranging from 25 weight percent up to about 35 weightpercent, based on the total weight of the vehicle.
 70. A method ofadministering a biologically active substance comprising administeringthe formulation of claim 64.